Mark W. Dodson, Kristina Allen-Brady, Jeffrey Stevens, Meghan M. Cirulis, Mona Alotaibi, Timothy M. Fernandes, Nick H. Kim, Kim M. Kerr, Demosthenes G. Papamatheakis, David S. Poch, Julianna Desmarais, D. Hunter Best, Nathan D. Hatton, John J. Ryan, C. Gregory Elliott, Lisa A. Cannon-Albright
Intermountain Medical Center. University of Utah and University of Utah School of Medicine. University of California San Diego. Oregon Health and Science University. ARUP Laboratories. George E. Wahlen Department of Veterans Affairs Medical Center.
United States
European Respiratory Journal Open Research
ERJ Open Res 2025; 11:
DOI: 10.1183/23120541.01322-2024
Abstract
Background: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is poorly understood. Studies of the genetic risk factors for CTEPH are likely to improve our understanding of CTEPH pathogenesis and may lead to novel treatment and prevention strategies. Genetic analysis focused on shared gene variants in high-risk disease pedigrees can aid in the identification of rare variants with a strong effect on disease risk.
Methods: We identified 13 CTEPH high-risk pedigrees and performed whole-exome sequencing in 22 CTEPH cases from these pedigrees, focusing on rare and deleterious variants that were shared between related CTEPH cases. We validated CTEPH candidate gene variants in two independent CTEPH cohorts, one from Utah (n=78) and one from the University of California San Diego (n=238), and compared them to controls from the UK Biobank.
Results: A rare and predicted deleterious missense variant in STAB2 was identified in two related CTEPH cases. Qualifying STAB2 variant alleles were observed more frequently in both CTEPH cohorts (pooled allele frequency 4.6%) than in subjects from the UK Biobank with a history of pulmonary embolism (PE) (allele frequency 2.2%, p=0.0002) or without a history of PE (allele frequency 1.9%, p<0.0001). CTEPH subjects with qualifying STAB2 variants had elevated levels of plasma von Willebrand Factor (vWF) and factor VIII, consistent with the known role of STAB2 as a genetic regulator of circulating vWF levels.
Conclusions: Rare variants in STAB2 are identified in a CTEPH high-risk pedigree and are over-represented in nonrelated CTEPH cases compared to controls with PE. These data suggest that STAB2 is a CTEPH risk gene.
Category
Class IV. Pulmonary Hypertension Associated with Thromboembolic Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes